Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells

Farnoodian, Mitra; Bose, Devika; Khristov, Vladimir; Susaimanickam, Praveen Joseph; Maddileti, Savitri; Mariappan, Indumathi; Abu‐Asab, Mones; Campos, Maria M; Villasmil, Rafael; Wan, Qin; Maminishkis, Arvydas; McGaughey, David; Barone, Francesca; Gundry, Rebekah L.; Riordon, Daniel R.; Boheler, Kenneth R.; Sharma, Ruchi; Bharti, Kapil

doi:10.1016/j.stemcr.2022.10.001

Cited by 17 publications

(20 citation statements)

References 52 publications

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“…ABCA4 is a membrane protein of the OS of PRs, however, cultured cells do not have an OS and some OS membrane proteins, like RHO 44 , are localized predominantly on the plasma membrane when heterologously expressed. ABCA4 has been reported to localize to the cell surface in HEK293T cells 40,45 , and in RPE cells derived from iPSCs 46,47 . Therefore, the plasma membrane localization of WT-ABCA4 and missense variants was investigated.…”

Section: Resultsmentioning

confidence: 99%

A proximity complementation assay to identify small molecules that enhance the traffic of ABCA4 misfolding variants

Piccolo,

Zarouchlioti,

Bellingham

et al. 2024

Preprint

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ABCA4–related–retinopathy is the most common inherited Mendelian eye disorder worldwide, caused by biallelic variants in the ATP-binding cassette transporter ABCA4. To date, over 2,200 ABCA4 variants have been identified, including missense, nonsense, indels, splice site and deep intronic defects. Notably, more than 60% are missense variants that can lead to protein misfolding, mistrafficking and degradation. Currently no approved therapies target ABCA4. In this study, we demonstrate that ABCA4 misfolding variants are temperature-sensitive and reduced temperature growth (30°C) improves their traffic to the plasma membrane, suggesting the folding of these variants could be rescuable. Consequently, an in vitro platform was developed for the rapid and robust detection of ABCA4 traffic to the plasma membrane in transiently transfected cells. The system was used to assess selected candidate small molecules that were reported to improve the folding or traffic of other ABC transporters. Two candidates, 4–PBA and AICAR, were identified and validated for their ability to enhance both wild-type ABCA4 and variant trafficking to the cell surface in cell culture. We envision that this platform could serve as a primary screen for more sophisticated in vitro testing, enabling the discovery of breakthrough agents to rescue ABCA4 protein defects and mitigate ABCA4–related–retinopathy.

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Section: Resultsmentioning

confidence: 99%

A proximity complementation assay to identify small molecules that enhance the traffic of ABCA4 misfolding variants

Piccolo,

Zarouchlioti,

Bellingham

et al. 2024

Preprint

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“…25 These have been localized in the RPE, ganglion cells, and rod photoreceptor cells, suggesting a retina-specific processing and maturation of HDL cholesterol. 26 Recently, the lipid profile of the RPE and the retina in general has been associated with STGD1, 27,28 further suggesting a possible link between HDL cholesterol and STGD1. Furthermore, mitochondrial function, for which sex differences have been shown and which has been suggested to play a role in diseases that involve the RPE such as STGD1, could be investigated more.…”

Section: Biological Sex Differences Possibly Impacting the Abca4-ar D...mentioning

confidence: 99%

Representation of Women Among Individuals With Mild Variants in ABCA4-Associated Retinopathy

Cornelis,

IntHout,

Runhart

et al. 2024

JAMA Ophthalmol

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ImportancePrevious studies indicated that female sex might be a modifier in Stargardt disease, which is an ABCA4-associated retinopathy.ObjectiveTo investigate whether women are overrepresented among individuals with ABCA4-associated retinopathy who are carrying at least 1 mild allele or carrying nonmild alleles.Data SourcesLiterature data, data from 2 European centers, and a new study. Data from a Radboudumc database and from the Rotterdam Eye Hospital were used for exploratory hypothesis testing.Study SelectionStudies investigating the sex ratio in individuals with ABCA4-AR and data from centers that collected ABCA4 variant and sex data. The literature search was performed on February 1, 2023; data from the centers were from before 2023.Data Extraction and SynthesisRandom-effects meta-analyses were conducted to test whether the proportions of women among individuals with ABCA4-associated retinopathy with mild and nonmild variants differed from 0.5, including subgroup analyses for mild alleles. Sensitivity analyses were performed excluding data with possibly incomplete variant identification. χ2 Tests were conducted to compare the proportions of women in adult-onset autosomal non–ABCA4-associated retinopathy and adult-onset ABCA4-associated retinopathy and to investigate if women with suspected ABCA4-associated retinopathy are more likely to obtain a genetic diagnosis. Data analyses were performed from March to October 2023.Main Outcomes and MeasuresProportion of women per ABCA4-associated retinopathy group. The exploratory testing included sex ratio comparisons for individuals with ABCA4-associated retinopathy vs those with other autosomal retinopathies and for individuals with ABCA4-associated retinopathy who underwent genetic testing vs those who did not.ResultsWomen were significantly overrepresented in the mild variant group (proportion, 0.59; 95% CI, 0.56-0.62; P &lt; .001) but not in the nonmild variant group (proportion, 0.50; 95% CI, 0.46-0.54; P = .89). Sensitivity analyses confirmed these results. Subgroup analyses on mild variants showed differences in the proportions of women. Furthermore, in the Radboudumc database, the proportion of adult women among individuals with ABCA4-associated retinopathy (652/1154 = 0.56) was 0.10 (95% CI, 0.05-0.15) higher than among individuals with other retinopathies (280/602 = 0.47).Conclusions and RelevanceThis meta-analysis supports the likelihood that sex is a modifier in developing ABCA4-associated retinopathy for individuals with a mild ABCA4 allele. This finding may be relevant for prognosis predictions and recurrence risks for individuals with ABCA4-associated retinopathy. Future studies should further investigate whether the overrepresentation of women is caused by differences in the disease mechanism, by differences in health care–seeking behavior, or by health care discrimination between women and men with ABCA4-AR.

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“…Besides inhibiting photoreceptor apoptosis to preserve vision, another approach is to target the compromised function and/or restore the dysregulated pathways associated with the mutated genes. A repurposed drug metformin has been shown to facilitate the clearance of lipid deposits caused by ABCA4 mutations in human pluripotent stem cell-derived and in vivo RPE ( Amin et al, 2022 ; Farnoodian et al, 2022 ). A selective estrogen receptor modulator raloxifene is also shown to inhibit photoreceptor apoptosis and mitigate toxicity of retinaldehyde in ABCA4 -associated models ( Getter et al, 2019 ).…”

Section: Recent Advances In Therapiesmentioning

confidence: 99%

Cell-cell interaction in the pathogenesis of inherited retinal diseases

Du,

Butler,

Chen

2024

Front. Cell Dev. Biol.

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The retina is part of the central nervous system specialized for vision. Inherited retinal diseases (IRD) are a group of clinically and genetically heterogenous disorders that lead to progressive vision impairment or blindness. Although each disorder is rare, IRD accumulatively cause blindness in up to 5.5 million individuals worldwide. Currently, the pathophysiological mechanisms of IRD are not fully understood and there are limited treatment options available. Most IRD are caused by degeneration of light-sensitive photoreceptors. Genetic mutations that abrogate the structure and/or function of photoreceptors lead to visual impairment followed by blindness caused by loss of photoreceptors. In healthy retina, photoreceptors structurally and functionally interact with retinal pigment epithelium (RPE) and Müller glia (MG) to maintain retinal homeostasis. Multiple IRD with photoreceptor degeneration as a major phenotype are caused by mutations of RPE- and/or MG-associated genes. Recent studies also reveal compromised MG and RPE caused by mutations in ubiquitously expressed ciliary genes. Therefore, photoreceptor degeneration could be a direct consequence of gene mutations and/or could be secondary to the dysfunction of their interaction partners in the retina. This review summarizes the mechanisms of photoreceptor-RPE/MG interaction in supporting retinal functions and discusses how the disruption of these processes could lead to photoreceptor degeneration, with an aim to provide a unique perspective of IRD pathogenesis and treatment paradigm. We will first describe the biology of retina and IRD and then discuss the interaction between photoreceptors and MG/RPE as well as their implications in disease pathogenesis. Finally, we will summarize the recent advances in IRD therapeutics targeting MG and/or RPE.

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Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells

Cited by 17 publications

References 52 publications

A proximity complementation assay to identify small molecules that enhance the traffic of ABCA4 misfolding variants

A proximity complementation assay to identify small molecules that enhance the traffic of ABCA4 misfolding variants

Representation of Women Among Individuals With Mild Variants in ABCA4-Associated Retinopathy

Cell-cell interaction in the pathogenesis of inherited retinal diseases

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